Korean J Urol Oncol 2014;12(2):47-53 전립선조직검사적응증 부산대학교의학전문대학원비뇨기과학교실 구자윤ㆍ전태경ㆍ하홍구 Indication of Prostate Biopsy Ja Yoon Ku, Tae Kyung Jern, Hong Koo Ha Department of Urology, Pusan National University School of Medicine, Busan, Korea The prevalence of prostate cancer is stiffly increasing in Korea. In contrasts to the frequency of occurrence, there is no definite guideline for the cut off value of serum PSA. So, we reviewed the usefulness of serum PSA and recently reported guidelines in the prostate cancer detection. Nowadays, the cut off value of PSA continued to change, moreover, it is difficult to satisfied both sensitivity and specificity, at the same time. Also, the value of PSA relies on the assay method or laboratory. Various methods such as the percent of free PSA, PSA velocity and PSA doubling time have been used to enhance the detection rate during prostate biopsy. However, these methods did not make certainty in deciding whether performing the prostate biopsy. To complement the uncertainty of PSA and its derivatives, the new ways such as propsa, PCA3 and gene fusion have been recently documented. Currently, the clearly indication of prostate biopsy is placed in controversy. Therefore, in the future, new methods to overcome non-specificity of PSA should be considered. (Korean J Urol Oncol 2014;12:47-53) Key Words: Prostate specific antigen, Prostate cancer screening, Prostate needle biopsy, Values clarification, Prostate cancer, Indication 서 현재전립선암은한국에서가장급속도로늘고있는남성악성고형종물중하나로서중앙암등록본부의통계에따르면 2010년인구 10만명당 25.3명이발생하였다. 1 전립선암의발생빈도는이와같이매우급속히증가하고있으나전립선암의확진을위한선별검사로널리사용되고있는혈중전립선특이항원 (prostate specific antigen, 이하 PSA) 의정확한절단치에대한합의가없는실정이다. 이에저자 Received July 18, 2014, Revised July 28, 2014, Accepted August 10, 2014 Corresponding Author: Hong Koo Ha, Department of Urology, Pusan National University Hospital, 179, Gudeok-ro, Seo-gu, Busan 602-739, Korea. Tel: 82-51-240-7351, Fax: 82-51-247-5443, E-mail: hongkooha@naver.com 론 는혈중 PSA 절단치기준의변천사를살펴보고현재발표된전립선조직검사에대한최신의진료지침에대한리뷰와전립선암의진단에도움을줄수있는최근의진단지표에대해알아보고자한다. 전립선조직검사의적응증비정상적인 DRE 및 ( 또는혹은 ) 높은혈중 PSA를보이는경우전통적으로전립선조직검사를시행하는것이권장되고있다. 특히나종양이의심되는비정상적인 DRE소견은혈중 PSA와상관없이전립선조직검사가권장된다. 전립선조직검사를위한혈중 PSA 절단치에대한변천사 1991년 Catalona 등은 1,653명의건강한성인남성을대상 47
48 대한비뇨기종양학술지 : 제 12 권제 2 호 2014 으로한연구에서기존의직장수지검사 (digital rectal examination, 이하 DRE) 와경직장초음파를통한전립선암의선별검사보다혈중 PSA 절단치 4ng/ml를같이사용할경우전립선암을발견하는데더유용하다고보고하였다. 2 이연구는이후미국식약청이전립선암의선별검사로혈중 PSA의사용을승인하는계기가되었다. 하지만이후 Catalona 등은 914명의선별검사자원자를대상으로한연구에서전립선암이혈중 PSA 2.5-4.0ng/ml에서도약 22% 발견되어혈중 PSA 절단치를 2.5ng/ml로낮추어야한다고주장하였다. 3 이들은이연구에서발견된전립선암은모두임상적으로국소암이었고술후조직검사에서 81% 가국소암으로최종진단되었으며약 10% 만이작은크기의저등급 (low grade) 암으로 2.5-4.0ng/ml의혈중 PSA에서도임상적으로유의한암이대부분을차지하였다고하였다. 약 7년후 Thomson 등은 Prostate Cancer Prevention Trial (PCPT) 결과를분석하여혈중 PSA 4.0ng/ml 이하에서도전립선암이상당수에서발견되는것을다시한번확인하였으며, 혈중 PSA 4.0ng/ml를절단치로할경우약 75.5% 의전립선암을놓칠수있다고하였다. 또한이전 Catalona 등이주장한혈중 PSA 2.5ng/ml 절단치또한약 47.4% 의위음성을보일수있다고하였다. 또한글리슨점수 7점이상을공격적인인자로간주하였을경우이러한임상적으로유의한전립선암이혈중 PSA 4.0ng/ml 혹은 2.5ng/ml를절단치로할경우약 59.6% 및 24.4% 에서위음성을보였다. 이에혈중 PSA 절단치를더낮추어 1.0ng/ml로할경우민감도는 83.4로어느정도수용가능하지만특이도가 38.9로낮게되어불필요한전립선조직검사가불가피하였다. 따라서저자들은본연구를통하여높은민감도와높은특이도를보이는혈중 PSA 절단치는존재하지않는다고주장하였다. 최근에유럽비뇨기과학회에서발표된진료지침에서도혈중 PSA는연속된변수로서높을수록전립선암의존재가능성이높다고하였으나정확히어느혈중 PSA 절단치를사용해야되는지는특정하지않고있다. 미국비뇨기학회의진료지침에서도혈중 PSA 는전립선암특이지표가아니며, 높은혈중 PSA는전립선조직검사의적응증이된다라고만언급하고있다. 혈중 PSA의검사에따른변화혈중 PSA의경우다른 PSA 방법 (assay) 을사용하면결과가달라질수있어주의가필요하다. 많은검사실에서질관리를통해검사실간의차이를줄이고자하고있지만 WHO 에서보정한등몰용액에서검사한 PSA에서도 20% 이상의차이가보고되고있다. 4 이러한차이점은다른연구에서도보고되고있어혈중 PSA를통한조직검사시행시반드시 동일한검사실에서동일한방법으로연속적으로시행하는것이권장되고있다. 5,6 또한동일한검사실및동일한방법을이용한검사에서도동일인에서약 20% 정도의생물학적변동을보인다고알려져있다. Soletormos 등은 50세이상남성에서혈중 PSA가 0.1-20ug/l인환자에서평균약 20% 정도의변동을보였다고보고하였으며, 7 다른연구에서는높은혈중 PSA를보인환자의 1/3에서재검시정상범위를보였다고하여 8 단일혈중 PSA만가지고전립선조직검사를시행하는것은무리가있다. 전립선조직검사의양성예측율을높이는방법 Okotie 등은약 36,000명의환자를대상으로 DRE와혈중 PSA 절단치를 2.5 및 4.0ng/ml로하여전립선암의선별검사를시행한결과절단치이하의혈중 PSA를보이는환자에서 DRE만이조직검사의지표로삼을수있다고하였다. 9 또한 DRE만으로진단된환자 303명중 20% 는국소진행성혹은글리슨점수가 7점이상으로공격적인양상을보였다고하여 DRE의진단적가치를높게평가하였다. 또한절단치이상의혈중 PSA와 DRE 이상소견을보인환자는그렇지않은환자에비해불량한예후를보이는경우가많았다고하여 DRE는임상적으로공격적인환자를찾을수있고선별검사에 DRE를불포함시키는것은향후치료결과에나쁜영향을미칠수있다고하였다. Gosselaar 등은상승된혈중 PSA와 DRE소견조합을사용하면글리슨점수 7점이상의전립선암을진단하는데도움이된다고하였다. 10 Catalona 등은혈중 PSA가 4-10ng/ml인환자에서유리 PSA백분율 (percentage of free PSA, 이하 %free PSA) 을사용하여절단치를 10으로할경우조직검사에서전립선암이발견될확률이 56% 로올릴수있으며, 2.5-4ng/ml인혈중 PSA에서도 %free PSA 절단치를 10으로하였을경우전립선암을발견할가능성이 46% 로높아졌고민감도및특이도가각각 30 및 94로보고하였다. 11 또한 %free PSA의경우나이에상관없이사용할수있는장점이있었다. 연령에따른 PSA치는실제임상에서직관적으로바로조직검사를시행할지말지를결정할수있는장점이있으나 50대이하에서는불필요한조직검사를시행할가능성과 70 대이상의고령에서는전립선암을놓칠수있는단점이있다. 12 전립선조직검사시행여부결정에있어혈중 PSA의변화량을수치화한 PSA velocity ( 이하 PSAV) 및 doubling time ( 이하 PSADT) 에대해서는다양한이견이존재하고있다. Tang 등의각인종별 PSA와 PSAV에대한연구에서는 50세미만의중국인, 미국계아프리카인및백인을대상으로하
구자윤외 : 전립선조직검사적응증 49 여비교하였을때중국인에서다른두인종에비해낮은기저 PSA 수치를보였으며 PSAV는다른두인종에비해높았고미국계아프리카인과백인에서는 PSA 수치와 PSAV 에있어통계학적인차이는보이지않았다고보고하여인종간의차이가능성을시사하였다. 13 그리고 Rundle 등은비만환자에서 PSAV 에대한연구를시행하여체질량지수 ( 이하 BMI) 가 35인사람에비해 BMI 25에서 PSAV가 13% 낮게측정되었고, 이연구에서만들어진공식에따르면 BMI가 4 증가할때 PSAV는 25% 감소를예측할수있다고하여전립선암에의한 PSAV 변화이외다른원인으로인한 PSAV의변동가능성을보여주었다. 14 이렇듯 PSAV를고려함에있어여러가지인자들이영향을미칠수있음을충분히인지해야할것이다. 유럽에서발표된 ERSPC 자료를분석한 Schroder 등에의하면전립선암의진단을위한 PSAV 는의미가없는것으로보고된 15 반면, 미국역학자료를바탕으로한 Berger 등은기존의 PSAV 0.7ng/ml/yr이아닌 0.4ng/ml/yr로할경우전립선암의진단에도움을준다고하여상반되는결과를발표하였다. 16 PSADT에있어서도 Sengupta 등은의미있는전립선암의진단에도움을준다고보고한 17 반면 Freedman 등은전립선암의진단에있어 PSADT의역할은매우제한되어있다고하였다. 18 이러한 PSAV와 PSADT에대한논란에대한 Dr Scaldino가밝힌최근의의견은높은 PSAV와짧은 PSADT만으로조직검사를시행하는적응으로하기에는무리가있으며, 단지이러한경우혈중 PSA를좀더자주시행할것을주문하여예전에비해전립선조직검사시행여부에있어 PSAV와 PSADT의중요성이약해진분위기이다. 다만, 혈중 PSA의변화 (PSAV 및 PSADT) 는진행된전립선암의치료후경과관찰에도움이되며단독으로조직검사시행여부를결정할것아니라 PSAV가포함된 nomogram을통한환자상담이이루어져야된다고하였다. 19 이러한 PSA derivatives를통한전립선암의진단에있어각각의연구에서서로상이한결과를보여주는가운데스페인인구조사에서 %freepsa의전립선암양성예측율이가장높았으며 Gleason score 7점이상의의미있는암에대해서는 PSAD가가장유용하였다는보고가있었다. 20 언급한것과같이전립선암의진단에있어 PSA와 DRE 및여러 PSA derivatives에대한일치되지못한연구결과는이모든인자들을하나의공식 (nomogram) 으로묶는경향을낳았다. 21 이러한 nomogram 또한등록된환자가연구마다이질적인경향이있어약간씩차이는보이지만환자와의상담에있어도움이될것으로보인다. 현재보고되고있는다수의 nomogram들은혈중 PSA 단독으로는 AUC가 0.02-0.26 정도이지만나이, 가족력, DRE소견및기타 PSA derivatives를포함할경우 AUR이 0.7 이상으로보고되어기존의혈중 PSA 혹은기타 PSA derivatives 단독으로전립선조직검사를시행하는것보다양성예측율을높일수있는것으로알려져있다. 22 최근의진료지침 (Table 1) 유럽비뇨기학회에서는비정상적인소견을보이는 DRE 나혈중 PSA가상승된경우조직검사를시행하라고하고있으나정확한혈중 PSA의절단치에대해서는제시하지않고있으나젊은연령의경우혈중 PSA 절단치를낮추는것을권고하고있다. 또한한번의혈중 PSA 상승만으로조직검사를바로시행하지말고수주후동일한조건하에동일한검사법으로재검하여혈중 PSA의상승이확인된경우조직검사시행을권장하고있다. 미국비뇨기학회에서도혈중 PSA와 DRE소견을통해조직검사를시행하는것을권장하고있지만정확한혈중 PSA 절단치에대해서는정확한언급이없다. 유럽비뇨기학회와미국비뇨기학회와는달리 NCCN 진료지침에서는비교적실제임상에서바로사용할수있는지침을발표하였는데비정상적인 DRE소견이보이는경우와혈중 PSA가 10ng/ml 이상에서는조직검사를시행하라고하고있고, 4-10ng/ml인 gray zone에서는가급적 (prefer) 조직검사를권장하고있으며, 2.5-4ng/ml에서는 PSAV를고려하여시행하는것을권장하고있다. 미국암협회에서는전립선조직검사와 PSA 검사에있어서검사의위험성과이득을고려하여 50세이상에서시행되어야하고, 전립선암의가족력이있거나아프리카계미국인일경우고위험군으로 40세이상에서시행하기를권고하였다. 그리고조직검사를시행함에있어 40세미만에서는 0.6ng/ml, 60세미만에서는 2.5ng/ml로 PSA 절단치를제시하였다. 그리고 NCCN 진료지침에서는검사에대한위험성과필요성에대해의논한후 40세부터 DRE와 PSA검사시행을권고하였다. 최근의여러진료지침에서는전립선암의선별검사에있어서공통적으로환자와의사간의의사결정의공유 (shared decision-making approach) 를대체적으로권장하고있다. 23 이러한의사결정의공유에있어서는환자와전문가와의상담을통해선별검사의시행유무부터시행하였을경우와시행하지않았을경우에예상되는결과등에대해충분한논의가이루어져야할것으로보인다. 혈중 PSA의비선택성으로인한딜레마미국 Preventive Service Task Force (USPSTF) 가혈중 PSA
50 대한비뇨기종양학술지 : 제 12 권제 2 호 2014 Table 1. Clinical guidelines to prostate biopsy Organization PSA cut off and DRE Considering factors EAU AUA American Cancer Society NCCN JUA Australian Cancer Network Systemic Development of Clinical Practice Guideline European Society for Medical Oncology Clinical Practice An abnormal DRE or elevated PSA (no exact cut-off value for normal PSA) For young men, PSA values <2-3ng/ml are often used The first elevated PSA level should not prompt an immediate biopsy, to be verified after a few weeks by the same assay under standardised conditions Based on PSA and DRE results, but no longer recommending a single threshold value of PSA PSA without DRE (when PSA >4ng/ml) or with DRE (when PSA 2.5-4.0ng/ml) Abnormal DRE (regardless of PSA): biopsy PSA >2.5ng/ml and PSA velocity >0.35 ng/ml/year: consider biopsy PSA 2.6-4.0ng/ml: consider biopsy PSA 4-10ng/ml: biopsy (preferred) PSA 4-10ng/ml and percent free PSA <10%: biopsy PSA >10ng/ml: biopsy The cut-off of PSA test level for the biopsy indication is recommended at 4.0ng/ml Alternative cut-offs for the biopsy indications are age-specific reference ranges of PSA The absolute level of PSA at which a biopsy may be recommended varies for each patient and depends on risk factors Recommended when the diagnosis leads to a treatment that will improve both the patient s quantity or quality of life and when total PSA is >4ng/ml Total PSA cut-off may be lowered to 2.5 ng/ml when indicated by other risk factors PSA should be measured and DRE performed in appropriately counselled patients in whom there is clinical suspicion of PCa or in those who want to be screened Biologic age, potential comorbidities (ASA index and CCI), and therapeutic consequences Risk stratification: important tool for reducing unnecessary biopsies Standardised condition of the verified PSA: no ejaculation and no manipulations, such as catheterisation, cystoscopy, or TUR, and no UTI Free and total PSA, patient age, PSA velocity, PSA density, family history, ethnicity, prior biopsy history, and comorbidities PSA level >4.0ng/ml: remains a reasonable approach for men at average risk PSA levels 2.5-4.0ng/ml: need to consider an individualised risk for high-grade cancer Risk factors include African American race, family history, increasing age, and abnormal DRE Age (men >75yr of age should be considered individually), comorbid conditions, percent free PSA, prostate exam/size, strength of family history, and African American ethnicity Age-specific reference ranges of PSA, which are set at 3.0, 3.5, and 4.0ng/ml in the age ranges of 50-64, 65-69, and >70yr of age, respectively Age, prostate size, family history, change in PSA over time, and (crucially) and DRE Two online risk calculators are available that bring these factors together into a single risk estimate (need to be used with caution and in discussion with the physician) Familiarity (at least one first-degree relative <60yr of age affected by PCa) or abnormal DRE or low ratio of free to total PSA (<10%) In PSA range of 4-10ng/ml, ratio of free to total PSA In evaluating patients treated for at least 3 mo with finasteride or dutasteride, total PSA values must be doubled or values discharged and considered as pretreatment values only Free PSA, PSA velocity and PSA density, DRE findings, prostate size, ethnicity, age, and comorbidities
구자윤외 : 전립선조직검사적응증 51 의선별검사의효용성에대한회의를제기한이후 Aslani 등의보고에의하면미국전역에서혈중 PSA 선별검사의비율이점차감소하고있는것으로나타났다. 24 이러한보고결과는 USPSTF의영향력이실제임상에서얼마나큰영향을미치는지반증하는결과라고할수있겠다. 하지만현재비뇨기의사가과연전립선조직검사를시행하느냐마느냐에있어명백한임상적지표가없는실정에서이러한 USPSTF의결과를비판없이따른다면또다른위험에봉착할수있다. 2004년 JAMA에보고된하나의예시로전립선암의진단에서환자와의충분한설명과상담후혈중 PSA 의검사를연기하다가나중에진행된전립선암이발견되어이에대한치료를시행했음에도불구하고법적인책임을지게된사연은한국에서도충분이개연성을지닌것으로보인다. 25 현재비뇨기의사로서이러한전립선암의진단을위한혈중 PSA에대한딜레마를해결하기위해서는일반대중에대한장기간의대단위결과와임상적으로의미있는고위험전립선암을예측할수있는지표가확립되어야하며, 또한근치치료에대한적절한환자의선택방법에대한조율이선행되어야될것이다. 하자고주장하였으나 30 아직연구가필요하다. 유전자재배열 (genetic rearrangement) 는암유전자의제일초기반응으로서 TMPRSS2와 ETS 전사인자유전자가전립선암환자에서발견되었는데 TMPRSS2가 ETS 계열의 ERG와결합 (fusion) 하는것이전립선암환자의약 40-70% 에서발견되었다. ERG는전립선암유발유전자중가장중요한것으로현재인식되고있으며이러한 TMPRSS2-ERG 결합은전립선암의고유병율을고려시인체고형암과관련된가장흔한유전자일탈로고려되어지고있다. 31 PCA3와마찬가지로 TMPRSS2-ERG 재배열은 DRE후소변에서측정이가능하다. 이렇게채취된소변에서 TMPRSS-ERG 재배열의전립선암에대한특이도는 0.90 이상으로나타나고양성예측도는 0.94를넘어서는것으로보고되어매우높은진단율이보고되고있다. 32 또한다른연구에서는 TMPRSS2- ERG fusion이보다공격적이고고병기의전립선암에서발현도가높게나타난다고보고하여이방법을통해진단된전립선암의의미가더높다고하였다. 33 결론 최근의새로운지표들최근연구에의하면 propsa, PCA3 및 gene fusion이전립선조직검사의주요한지표가될가능성이보여지고있다. propsa는 PSA의전구체로서 [-2]proPSA는양성세포보다암세포에서좀더호발하는것으로알려져있다. Guazzoni 등은 free PSA에대한 [-2]proPSA의비율 ( 이하 %[02]proPSA) 이기존의 PSA, free PSA 및 %free PSA에비해전립선암의진단에있어도움이된다라고보고하였고, 26 이러한연구결과는유럽지역다기관연구에서다시한번확인되었다. 27 또한이후연구에의하면혈중 PSA가 2-10ng/ml인환자에서 %[-2]proPSA를사용할경우전립선발견빈도가의미있게높게나타났다고하여혈중 PSA가 gray zone에위치한환자에서조직검사시행여부를결정하는데도움이될것으로보인다. PCA3는전립선암세포에서높게발현되며혈중 PSA, DRE 및전립선크기와는독립적인인자로알려져있으며혈중 PSA, PSA density 및 %freepsa보다전립선조직검사결과를더잘예측하는것으로보고되고있다. 28,29 하지만 PCA3에도절단치가존재하여어떠한환자에서조직검사를유도해야되는데에아직 debate가남아있다. 최근 Capoluongo 등에의하면 PCA3 score를 20을절단치로하였을경우민감도가 0.954이고음성예측치가 0.975로매우높게나와의미가있었다고하여 PCA3 score 20을절단치로 전립선암을정확한진단을위해서현재혈중 PSA를비롯하여 DRE 및여러 PSA derivatives가연구되었으나아직명확한진료지침도없는등한계가많은실정이다. 이에이러한여러인자를한꺼번에고려한 nomogram을사용하기도하지만아직임상에서사용하기에는불편한사항이많은것이사실이다. 하지만, 아직도혈중 PSA는전립선조직검사시행여부를결정할때중요한인자임에는틀림없으나현재사용되고있는 PSA의비특이성을극복할수있는전립선암진단지표가향후마련되어야될것으로생각되며, 최근연구되고있는 [-2]proPSA, PCA3 및 TMPRSS2-ERG fusion의결과를고려한다면향후수년후에는조직검사여부를결정할때이러한인자들이유용하게사용될것으로기대한다. REFERENCES 1. National CANCER CENTER Cancer Facts & Figures. 2013. p. 13 2. Catalona WJ, Smith DS, Ratliff TL, et al. Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med 1991;324:1156-61 3. Catalona WJ, Smith DS, Ornstein DK. Prostate cancer detection in men with serum PSA concentrations of 2.6 to 4.0 ng/ml and benign prostate examination. Enhancement of specificity with free PSA measurements. JAMA 1997;277:1452-5
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